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A Spleen Tyrosine Kinase Inhibitor Reduces the Severity of Established Glomerulonephritis

Jennifer Smith^*, John P. McDaid^*, Gurjeet Bhangal^*, Ratana Chawanasuntorapoj^*,, Esteban S. Masuda, H. Terence Cook^*, Charles D. Pusey^* and Frederick W.K. Tam^*

*Imperial College Kidney and Transplant Institute, London, United Kingdom;
Renal Division, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand; and
Rigel Pharmaceuticals, South San Francisco, California

Correspondence: Dr. Frederick W.K. Tam, Imperial College Kidney and Transplant Institute, Division of Medicine, Hammersmith Hospital, Du Cane Road, London W12 0NN, United Kingdom. Phone: 44-20 8383 2354; Fax: 44-20 8383 2062; E-mail: f.tam{at}imperial.ac.uk

Received for publication March 9, 2009. Accepted for publication October 19, 2009.

Antibody-mediated glomerulonephritis, including that resulting from immune complexes, is an important cause of renal failure and is in need of more specific and effective treatment. Binding of antibody or immune complexes to Fc receptors activates intracellular signal transduction pathways, including spleen tyrosine kinase (Syk), leading to the production of inflammatory cytokines. We examined the effect of R788 (fostamatinib disodium), an oral prodrug of the selective Syk inhibitor R406, in nephrotoxic nephritis in Wistar-Kyoto rats. Treatment with R788 reduced proteinuria, tissue injury, glomerular macrophage and CD8+ cell numbers, and renal monocyte chemoattractant protein-1 (MCP-1) and IL-1β, even when we started treatment after the onset of glomerulonephritis. When we administered R788 from days 4 to 10, glomerular crescents reduced by 100% (P < 0.01) compared with the vehicle group. When we administered R788 treatment from days 7 to 14, established glomerular crescents reversed (reduced by 21%, P < 0.001), and renal function was better than the vehicle group (P < 0.001). In vitro, R406 downregulated MCP-1 production from mesangial cells and macrophages stimulated with aggregated IgG. These results suggest that Syk is an important therapeutic target for the treatment of glomerulonephritis.

Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673